KR102387840B1 - Antihistamines for the treatment of breast cancer - Google Patents

Abstract

Disclosed herein is desloratadine or ebastine for use in the treatment of a patient diagnosed with breast cancer. Also disclosed is desloratadine or ebastine for use in the treatment of a patient diagnosed with a cancer type susceptible to immunotherapy.

Description

Antihistamines for the treatment of breast cancer

The present invention generally belongs to the field of breast cancer treatment. More particularly, the present invention relates to a medicament for the treatment of breast cancer.

Breast cancer is one of the more common types of cancer among women, and it is known that one in eight women will develop it during their lifetime. Risk factors for breast cancer include sex, age, genetics, individual factors, and other risks, such as being overweight, using hormone replacement therapy (also called menopause hormone therapy), taking birth control pills, drinking alcohol, never giving birth or after age 35. Contains acetic acid or dense breasts.

Symptoms of breast cancer may include lumps in the breast, changes in the size and shape of the breast, or nipple discharge. Breast self-examination and mammography can aid in the detection of early breast cancer that is mostly treatable. Treatment of primary breast cancer usually consists of surgery followed by adjuvant therapy (radiotherapy, chemotherapy, hormone therapy, etc.).

Various types of treatment are available for breast cancer patients. Most breast cancer patients undergo surgery to remove cancer from the breast, and many different surgical procedures exist for breast cancer removal. Other treatments include radiation therapy, which is a cancer treatment that uses high-energy x-rays or other types of radiation to kill or prevent cancer cells from growing. Chemotherapy is a cancer treatment that uses drugs that stop the growth of cancer cells by killing them or stopping them from dividing. Hormone therapy is a cancer treatment that stops the growth of cancer cells by removing hormones or blocking the action of the hormones. Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells, for example using monoclonal antibodies and tyrosine kinase inhibitors.

The World Health Organization (WHO) 2014 World Cancer Report reports that breast cancer is the second most common cancer in the world, accounting for over 1 million new cases each year. The report states that in 2000 (the last year for which global data exist) approximately 400,000 women died of breast cancer, accounting for 1.6 percent of all female deaths. The rate of breast cancer deaths was significantly higher in wealthy countries (2 percent) than in economically poor areas (0.5 percent of all female deaths). Thus, breast cancer is strongly associated with Western lifestyles. As developing countries continue to achieve lifestyles similar to those of Europe, North America, Australia, New Zealand and Japan, they will also encounter much higher rates of cancer, particularly breast cancer. Recent data support this prediction, showing a 20% increase in breast cancer rates from 2008 to 2012 (Carter D. "New global survey shows an increasing cancer burden". Am J Nurs. 2014 Mar; 114(3): 17).

Therefore, there is a strong demand for new types of breast cancer treatment. Although new treatments should be aimed at curing breast cancer, it would also be beneficial to improve the prognosis for patients diagnosed with breast cancer or increase survival time for patients diagnosed with breast cancer.

Summary of the invention

It is an object of the present invention to provide a treatment for a patient diagnosed with breast cancer, which improves the prognosis and increases the breast cancer-related survival time of the patient, taking into account the above-mentioned disadvantages.

The above and other objects which will become apparent from the following description have been achieved in the present invention by an H1 receptor antihistamine for use in the treatment of breast cancer, wherein the H1 receptor antihistamine is desloratadine or ebastine.

The breast cancer is selected from the group consisting of benign and negative ER, PR, her2 breast cancer molecular subtype, and invasive breast cancer. On the one hand, it is selected from the group consisting of benign and negative ER invasive breast cancer.

The treatment continues for at least 50 days, preferably at least 100 days and most preferably at least 400 days. The treatment is intended to improve the prognosis for a patient diagnosed with breast cancer and/or increase the survival time for a patient diagnosed with breast cancer.

The daily dose of the H1 receptor antihistamine corresponds to the defined daily dose (DDD). When the H1 receptor antihistamine is desloratadine, the dose of desloratadine is 2.5 to 45 mg per day, preferably 5 to 20 mg per day, most preferably 5 mg per day. When the H1 receptor antihistamine is evastin, the dose of ebastin is 2.5 to 100 mg per day, preferably 5 to 40 mg per day, and most preferably 10 mg per day.

In the use of treatment as described above, the patient is not diagnosed with a seasonal allergic condition, is perioperational, or is treated with radiotherapy, chemotherapy and/or hormone therapy.

Also provided is an H1 receptor antihistamine for use in the treatment of a type of cancer that is sensitive to immunotherapy.

The following terms are used herein:

AH antihistamines

BR breast cancer

CI confidence interval

ER estrogen receptor

HR risk ratio

PR progesterone receptor

HER2 human epidermal growth factor receptor 2

Database mining has proven to be a very powerful tool for discovering invisible tendencies in treatment outcomes. The Swedish Drug Register contains data on drugs prescribed in pharmacies, supply quantities and food or equivalents since 1999. The number of prescriptions is nearly 100 million a year. The register is updated monthly with new information. The Swedish Cancer Registry was established in 1958 and covers the entire population of Sweden. Approximately 50 000 cases of malignant cancer are registered each year in Sweden. It is compulsory for all health care providers to report newly discovered cases of cancer to the registry. Reports should be sent not only for cases diagnosed at autopsy, but also for all cancer cases diagnosed clinically, morphologically, and with other laboratory tests. Thus, these registries provide a very good foundation for mining databases that are researched from international standards.

The study underlying this invention uses data from the National Register and elsewhere, spanning eight years without bias. The registry used is of good quality with all medical records from 2005, which is an important indicator of drug use, especially for people who have been prescribed the same drug multiple times.

Investigating treatments related to improving survival of breast cancer patients, the inventors of the present invention found that treatment with H1 receptor antagonists, particularly desloratadine or ebastin, has a positive effect on breast cancer survival, as can be seen in Figures 1-3. The surprising results were found to have a positive effect.

A replicate study was performed using expanded breast cancer data of all cases from the Swedish Cancer Registry 2000-2013 (n=103 500 cases) linking the data to the drug prescription registry. Data from this expanded study can be found in Tables 10 and 11. With larger data sets, the effect of each individual antihistamine becomes more robust. It is clear that an overall effect on better breast cancer survival exists with desloratadine and ebastine. Table 11 summarizes the above effects for desloratadine. Looking at the years prior to 2009, the survival is significantly improved for desloratadine users compared to non-users, HR = 0.63.

Table 10 further shows that the H1 receptor antagonists clemastine and ceterizine have a negative effect on BC survival (HR = 1.2 and HR = 1.28), indicating a clear difference between studies using real patient data and in vitro studies. highlight the difference. In an in vitro test described in US 2004/0072824 A1, it was suggested that clemastine has an in vitro cytotoxic effect on cancer cell lines. Similarly, WO 2004/080445 A1 suggests that clemastine has an in vitro cytotoxic effect and that clemastine and cetrizine can be used to inhibit the growth of cancer cells. However, the actual patient data of the present invention, presented in Table 10, show that the possible general cytotoxic effects of clemastine and cetrizine do not provide any improved BC survival in vivo. In contrast, the use of these anti-histamines ostensibly lowers the BC survival rate.

Accordingly, in a first embodiment of the present invention, desloratadine or ebastine, which is an H1 receptor antihistamine, is used for the treatment of breast cancer.

This was surprising because the antihistamine is structurally similar to DPPE, a tamoxifen derivative known to promote tumor growth. This has historically been known as a risk factor for breast cancer, and animal experiments have shown that several antihistamines in mice (Brandes LJ et al. "Enhanced cancer growth in mice administered daily human-equivalent doses of some HI-antihistamines: predictive in vitro correlates") J Nat Cancer Inst 1994;86:770-5.) and antidepressants (Brandes, LJ et al. "Stimulation of malignant growth in rodents by antidepressant drugs at clinically relevant doses." Cancer Res 1992;52:3796-800) associated with enhanced tumor growth.

However, few epidemiologic studies investigating antihistamines have been conducted. These studies were aimed at the evaluation of breast cancer risk. The above, however, did not point to an increased risk of breast cancer. There are even statistical studies that have concluded that women who use antihistamines do not have a greater risk of breast cancer than women who do not use them (Nadalin, V. et al. "Antihistamine use and breast cancer risk". Int. J. Cancer: 106, 566-568, (2003)). Therefore, the field has not come to a conclusion.

When looking at individual H1 receptor antagonists, the study showed that antihistamines in women with breast cancer (BC) using clemastine, loratadine, desloratadine, evastine and fexofenadine in an ever-use model. It can show a clear benefit from the first treatment. As can be seen from Figures 2 and 3, these women had a distinct, statistically significant, longer BC-specific survival compared to controls, particularly from desloratadine and ebastine treatment.

This positive effect is observed in different breast cancer molecular subtypes, for example, both positive and negative ER, as can be seen in Tables 8 and 9. This is equally surprising since the ER negative subtype is considered very difficult to treat. However, although it would be very conceivable that the effect also relates to other breast cancer molecular subtypes, eg PR and her2 subtypes, the effect on these subgroups cannot be extracted from the data register. In one embodiment of the present invention, said breast cancer comprises benign and negative ER invasive breast cancer. In another embodiment of the present invention, said breast cancer comprises positive and negative ER, PR, her2 breast cancer molecular subtype, and invasive breast cancer.

The improvements observed in breast cancer patients using the H1 receptor antihistamines desloratadine or ebastin include improved prognosis as well as increased survival. Accordingly, in one embodiment of the present invention, the treatment seeks to improve the prognosis for a patient diagnosed with breast cancer. In another embodiment of the invention, the treatment seeks to increase the survival time of a patient diagnosed with breast cancer.

H1-antihistamines are used clinically in the treatment of histamine-mediated allergic conditions. The term "antihistamine" refers to H1 antagonists (also known as H1-receptor antagonists and H1-antihistamines), which reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions acts to

To rule out the possibility that a patient's allergy might play a role in the positive effect on breast cancer survival when using H1 receptor antagonists, data analysis from outpatients and inpatients diagnosed with allergies was performed using antihistamines. It was still shown to improve this survival diagnosis (not shown). Indeed, literature examining allergies and cancer instead suggests that the risk for individual cancers such as breast-prostate and kidney cancers is increased by allergic conditions (Hemminki et.al. "Risk of cancer in patients with medically diagnosed hay fever or allergic rhinitis". Int. J. Cancer:135, 2397-2403 (2014)).

In one embodiment of the present invention, the H1 receptor antihistamine, desloratadine or ebastine, is for treatment of a patient diagnosed with breast cancer but not a seasonal allergic condition. In another embodiment of the present invention, the H1 receptor antihistamine, desloratadine or ebastin, is diagnosed with breast cancer but an allergic condition, e.g., an allergic condition in which H1 receptor antihistamine treatment is administered, typically for at least 6 consecutive months. For the treatment of patients not diagnosed with

A comparative terminal entry model is also used in our study to reduce the survival bias that comes from treatment initiated after BC diagnosis. This takes into account additional study subjects who participated during the study period. In the case of such late entry, the possibility exists that delayed entry has a different risk compared to other standard subjects. As can be seen from Figures 4 and 5, women who participated as terminal participants in this study using loratadine, desloratadine and ebastine had a statistically significant longer BC-specific survival compared to controls. . Similarly, women who participated as terminal participants in this study using cetrizine, clemastine and fexofenadine had a non-statistically significant longer BC specific survival compared to controls.

Desloratadine, loratadine or ebastine are all second-generation H1-antihistamines. Second-generation H1-antihistamines are newer drugs that are more selective for peripheral H1 receptors as opposed to central nervous system H1 receptors and cholinergic receptors. These are all highly polar compounds, meaning that they will not cross the blood-brain-barrier (BBB) and will primarily act outside the central nervous system.

There are a number of potential mechanisms mediating the observed effects. This effect is usually marked by desloratadine. This may be linked to the fact that it has the strongest affinity for the H1 receptor. It is also thought to have a greater effect on the immune system by influencing cytokine levels. Moreover, desloratadine has a much larger distribution volume than most other H1 antagonists, which results in a larger tissue distribution. This, coupled with the long half-life for desloratadine, will mean that daily desloratadine therapy provides a fairly complete blockade of basal H1 signaling in almost all tissues and all organs, eg tumors.

In this study, the drug regimen was judged on the basis of drug prescription. The information reflects fairly accurate usage, especially for people with multiple prescriptions. A confounding factor is the possibility of out-of-commercial purchases of cetirizine and loratadine, but this will only dilute any observed effects. However, desloratadine and clemastine were both prescription drugs during the study period.

Accordingly, in one embodiment of the present invention, the daily dose of desloratadine or evastin, which is the H1 receptor antihistamine, corresponds to a defined daily dose (DDD). The DDD is a statistical measure of drug intake, as defined by the World Health Organization (WHO).

6 shows the benefit of longer treatment durations in the standard dose regimen. It can be clearly established that women who have used desloratadine for more than 400 days have a distinctly better therapeutic effect than women who have used desloratadine for less than 400 days. In one embodiment of the invention, the treatment continues for at least 50 days, for example at least 100 days. The treatment may even continue for at least 400 days or longer.

7 establishes the treatment period associated with the diagnosis of breast cancer. For women who used desloratadine only prior to BC diagnosis, a positive effect on breast cancer survival could not be established. However, for a group of women who used desloratadine only after a BC diagnosis, an apparent positive effect could be seen. For women who used desloratadine both before and after BC diagnosis, a similar amount of effect could be seen, but the group was not large enough to establish a statistical significance level.

Although this study shows an advantage from antihistamine treatment at conventional dose regimens, other dose regimens, such as higher doses for perioperative treatment, are equally possible.

In one embodiment of the present invention, desloratadine or evastin, which is an H1 receptor antihistamine, is used for perioperative treatment of a patient diagnosed with breast cancer.

A possible benefit of the higher dose regimen is also shown by Figure 7, where the group using desloratadine both before and after the BC diagnosis showed an immediate positive effect, which resulted in a constant initial treatment period (which was may be shortened by ) imply that the treatment is required to be most effective.

Thus, in one embodiment of the present invention, the dose of desloratadine is from 2.5 to 45 mg per day, preferably from 5 to 20 mg per day, most preferably from 5 mg per day. A multi-dose study using 45 mg desloratadine per day did not show any additional clinical adverse events (FASS, Compendium of Medicines for Healthcare Professionals, Sweden). Accordingly, in one further embodiment, a high dose of desloratadine of 45 to 250 mg per day, preferably 85 to 150 mg per day, and most preferably 100 mg per day is administered.

In one embodiment of the present invention, the dose of ebastin is from 2.5 to 100 mg per day, preferably from 5 to 40 mg per day, most preferably from 10 mg per day. A multi-dose study using 100 mg of evastin per day did not show any additional clinical adverse events (FASS, Compendium of Medicines for Healthcare Professionals, Sweden). Thus, in one further embodiment, a high dose of ebastin is administered from 100 to 500 mg per day, preferably from 150 to 300 mg per day, most preferably from 200 mg per day.

An adjunct to the prescription of antihistamines is to relieve the side effects of chemotherapy. How this affects the outcome of the study is unknown, as we do not have access to chemotherapy data. However, from these reports, clemastine appears to be the drug of choice for this purpose. However, many BC patients in this study underwent conventional BC treatment with the use of H1 receptor antagonists. Thus, the positive effect of co-treatment with conventional BC treatment with H1 receptor antagonists has been clearly established.

Accordingly, in one of the present invention there is provided desloratadine or ebastine, an H1 receptor antihistamine for use in the co-treatment of a patient diagnosed with cancer, wherein the co-treatment is radiotherapy, chemotherapy, hormone therapy It further includes treatment by

In a further embodiment of the present invention, there is provided desloratadine or ebastine, a H1 receptor antihistamine, and a chemotherapeutic and/or hormonal agent for use in the co-treatment of a patient diagnosed with cancer.

In yet another embodiment of the present invention, there is provided a pharmaceutical formulation comprising desloratadine or evastin, which is an H1 receptor antihistamine, and a chemotherapeutic agent. The chemotherapeutic agent of the pharmaceutical formulation may be an anthracycline, a taxane or a platinum agent.

In still another embodiment of the present invention, there is provided a pharmaceutical formulation comprising desloratadine or evastin, which is an H1 receptor antihistamine, and a hormone agent. The hormonal agent may be tamoxifen, toremifene, fulvestrant or an aromatase inhibitor.

Immunotherapy of cancer has recently achieved remarkable success, particularly with the use of antibodies directed against T-cell regulatory targets. In patients with metastatic melanoma, long-term survival was achieved in 20% of these patients and a subgroup of patients could be cured. A subgroup of patients with triple negative or Her2-neu positive breast cancer is also thought to be candidates for immunotherapy. Research is ongoing to see if patients with other tumor types, such as kidney and lung cancer, may also be susceptible to immunotherapy. Preliminary data from large international conferences suggest interesting patient responses to therapies. Therefore, it is conceivable that immunotherapy may be successful in a small subgroup of most cancer types. Where the effect shown for an antihistamine is due to an immunological mechanism, tumor types other than breast cancer, such as malignant melanoma, breast cancer, renal cancer, lung cancer, hematological cancer, malignant lymphoma, prostate cancer, glioma, or Cervical cancer may have a positive survival effect in a similar manner.

In one embodiment of the present invention there is provided desloratadine or ebastine, which is an H1 receptor antihistamine for use in the treatment of a type of cancer that is sensitive to immunotherapy.

About 5% to 10% of breast cancer cases are thought to be hereditary, meaning that these cases result from genetic defects inherited directly from parents. The best known cause of hereditary breast cancer is inherited mutations in the BRCA1 and BRCA2 genes. Typically, these genes help prevent cancer by making proteins for the error-free DNA-repair process that prevents cells from growing abnormally. Other gene mutations, such as ATM, TP53, CHEK2, PTEN, CDH1, STK11 or PALB2, are also associated with inherited breast cancer. Numerous other known risk factors may also increase the risk of breast cancer 5- to 10-fold, for example, non-cancerous (benign) breast conditions, such as non-proliferative lesions or proliferative lesions (with or without atypicalities). exists) exists. Other changes detected in breast tissue (i.e., abnormal cells), such as intraepithelial lobular carcinoma (LCIS) and ductal carcinoma in situ (DCIS), will increase the risk for breast cancer or, in the case of DCIS, will eventually lead to cancer.

According to one embodiment, there is provided desloratadine or ebastine, an H1 receptor antihistamine for use in a pre-treatment, ie, prophylactic treatment, for a woman having a high risk factor for developing breast cancer.

Women diagnosed with breast cancer in one breast have a 3- to 4-fold increased risk of developing (recurring) the first cancer and other new cancers in the other breast or another part of the same breast.

According to one embodiment, an H1 receptor antihistamine for use in the pre-treatment, ie, prophylactic treatment, of a woman having cancer in one breast, who is at high risk of developing a new cancer in the same breast or another part of the breast. Desloratadine or ebastine is given.

Obviously, the H1 receptor antihistamines desloratadine or ebastin can also be used in the manufacture of a medicament for use in a treatment as disclosed herein, for example, the treatment of breast cancer. Similarly, desloratadine or ebastin, which are H1 receptor antihistamines, may also be expressly used in methods of treatment of diseases and conditions as disclosed herein, for example, treatment of breast cancer. The method includes administering an effective amount of the H1 receptor antihistamine, desloratadine or ebastin, to a subject in need of such treatment.

In the context of this specification, the terms "therapy" and "treatment" include prophylaxis or prophylaxis, unless specifically indicated otherwise. The terms “therapeutically” and “therapeutically” should be interpreted correspondingly.

According to one embodiment, treatment also includes pre-treatment, ie prophylactic treatment.

According to one embodiment, the term "prophylactic" or "prophylactic" includes primary prophylaxis, secondary prophylaxis, tertiary prophylaxis, or periodic prophylaxis, unless otherwise indicated. Primary prophylaxis refers to the prophylactic treatment of early disease. Secondary prophylaxis refers to reducing the incidence of recurrence or reactivation of an existing disease. Tertiary prophylaxis refers to continuous treatment started after the onset of the disease to alleviate further damage. Periodic prophylaxis refers to periodic prophylactic treatment given for a shorter period of time. For example, desloratadine or ebastin, which are H1 receptor antihistamines used for perioperative treatment, can be used in secondary prophylaxis to reduce the occurrence of recurrence or reactivation of existing breast cancer.

Thus, in one embodiment of the invention, treatment relates to primary prophylaxis, secondary prophylaxis, tertiary prophylaxis or periodic prophylaxis.

Although the present invention has been described above with reference to specific embodiments, it is not intended to limit the invention to the specific form set forth herein. Rather, the present invention is limited only by the appended claims, and other embodiments than the specific form above are equally possible within the scope of these appended claims, for example other than those described above.

In the claims, the term "comprises/comprising" does not exclude the presence of other elements or steps. Moreover, although individually listed, multiple means, elements or method steps may be performed by, for example, a single unit or processor. Additionally, although individual features may be included in different claims, these features may possibly be advantageously combined, and the inclusion in different claims does not imply that a combination of features is not possible and/or not advantageous. . Also, the singular referent does not exclude the plural. "A", "a first", "second", etc. do not exclude a plurality. References in the claims are provided as examples for clarity only and should not be construed as limiting the scope of the claims in any way.

These and other aspects, features and advantages possible by the present invention will become apparent from the following description of embodiments of the present invention with reference to the accompanying drawings, in which:
1 is a graph showing breast cancer survival according to the experience of using an antihistamine for allergy.
2 is a graph showing breast cancer survival according to the experience of using antihistamines of cetirizine, clemastine and loratadine.
3 is a graph showing breast cancer survival according to the experience of using antihistamines of desloratadine, ebastine and fexofenadine.
4 is a graph showing breast cancer survival according to the experience of using antihistamines of cetirizine, clemastine and loratadine in a terminal entry model.
5 is a graph showing breast cancer survival according to the experience of using antihistamines of desloratadine, ebastin and fexofenadine in a terminal entry model.
6 is a graph showing breast cancer survival according to the duration of use of desloratadine in a terminal participation model.
7 is a graph showing breast cancer survival when women used desloratadine in a terminal entry model.

Substances and methods

A cohort of all Swedish women without prior cancer and diagnosed with BC from 2000 to 2008 was used. The study was approved by the Swedish Ethics Committee. Date of birth, BC diagnosis and TNM-staging were collected from the Swedish Cancer Registry. Medication records of these women starting from 1 July 2005 were collected from the Swedish Pharmaceutical Registry. Dates of death were collected from the Swedish Population Register up to 31 December 2013. Causes of death were also collected from the Swedish population registry, but were only available until 31 December 2012. At the time of BC diagnosis, women over 50 years of age were considered postmenopausal, whereas women younger than 50 years old were considered premenopausal. Groups of women were created, all of whom were prescribed antihistamines for allergies, and then also separated into groups according to the most used antihistamines. The control group consisted of all women who were not prescribed antihistamines for allergies. In the experienced model, all women who were prescribed antihistamines from the Swedish Pharmaceutical Register from 1 July 2005 were included.

Staging of breast cancer is described using the American Council on Cancer (AJCC) TNM system. The TNM staging system classifies cancers based on their T, N, and M stages:

The letter T followed by a number from 0 to 4 describes the size of the tumor and its spread to the skin below the breast or to the chest wall. A higher T number means a larger tumor and/or wider spread to tissues closer to the breast.

A number from 0 to 3 following the letter N indicates whether the cancer has spread to lymph nodes near the breast and, if so, how many lymph nodes have been affected.

A 0 or 1 following the letter M indicates whether the cancer has spread to distant organs, such as the lungs or bones.

T-stage data were recorded as a set of variables from 1 to 5, with 1 to 4 corresponding to reported T-stage and 5 corresponding to missing T-stage. The N-stage data were recorded as a set of variables from 0 to 4, where 0 to 3 corresponded to reported N-stages and 4 corresponded to missing N-stages. M-stage was recorded as a variable of 0 and 2, with 0 corresponding to reported 0 M-stage and 2 corresponding to missing M-stage. All of the above data were from the Swedish Cancer Registry.

Because the experience of using antihistamines for allergies was investigated, most users brought their prescribed antihistamines after BC diagnosis. It was decided to investigate survival and risk in two ways: dividing the groups according to experience and secondly using a terminal entry model to reduce the survival bias in the first model. In the terminal participation model, all women with unknown N-status and all cases before July 1, 2005 were excluded to obtain more accurate results.

A replicate study was performed using expanded breast cancer data of all cases from the Swedish Cancer Registry 2000-2013 (n=103 500 cases) linking the above data with the drug prescription registry. Data from this expanded study are presented in Tables 10 and 11.

statistics

Statistical analysis was performed using IBM SPSS 22.0 and R Studio v 0.98.983.

Univariate BC specific survival was statistically predicted using Kaplan Meier for the group in which all antihistamine users were associated and for each specific antihistamine group. Distributions were tested using the log-rank test.

Hazard ratios (HR) were calculated using Cox proportional hazards. HR was calculated for each group of antihistamine users and included age at BC diagnosis (linear), T-stage (T1, T2, T3, T4, missing), N-stage (N0, N1, N2, N3, missing), Adjustments were made for M-stage (M0, M1, missing values). Multivariate analysis was also stratified for ER-status. HR was statistically predicted with a 95% confidence interval (CI). Two-tailed p-values were used for all analyses. A p-value of less than 0.05 was considered as statistical significance.

End-of-Participation Cox Proportional Hazards Analysis, HR, performed at the R studio above, calculated for each group of antihistamine users, including age at BC diagnosis (linear), T-stage (T1, T2, T3, T4, missing) and N- Adjustments were made to stage (N0, N1+). The analysis was also stratified for ER-status. HR was predicted with a 97.5% confidence interval (CI). Two-tailed p-values were used for all analyses. A p-value of less than 0.05 was considered as statistical significance.

result

The study included 47350 women with invasive BC. The patient characteristics are shown in Table 1. 18724 were included after 1 July 2005 when the Swedish Pharmaceutical Register was started. The characteristics of the patients can be seen in Table 2. Repeat studies including all BC cases from the Swedish Cancer Registry 2000-2013 (n=103 500 cases) are presented in Table 10.

(Table 1: Patient characteristics for women divided into groups according to main antihistamine used. Table includes all patients from 2000 to 2008.)

(Table 2: Patient characteristics for women divided into groups according to main antihistamine used. Table includes all patients from July 1, 2005 to December 31, 2008.)

User experience model

1 shows breast cancer survival according to the experience of using antihistamines for allergy. N=9777 in the No AH group and N=37573 in the AH group.

Univariate Analysis

Women using any type of H1 receptor antihistamine had a statistically significant longer BC-specific survival compared to controls ( FIG. 1 ). Women using clemastine, loratadine, desloratadine, ebastine and fexofenadine had a statistically significant longer BC-specific survival compared to controls. Women who used cetirizine initially had a higher survival rate compared to controls, but became lower compared to controls over time ( FIGS. 2 and 3 ). Figure 2 shows breast cancer survival according to the experience of using antihistamines of cetirizine, clemastine and loratadine. N=37573 in the No AH group, N=3001 in the cetirizine group, N=2278 in the clemastine group, and N=2132 in the loratadine group. 3 shows breast cancer survival according to the experience of using antihistamines of desloratadine, ebastine and fexofenadine. N=37573 in the No AH group, N=1895 in the desloratadine group, N=326 in the ebastine group, and N=145 in the fexofenadine group.

Multivariate Analysis

The HR for the group of antihistamine users adjusted for age at diagnosis of BC and TNM was 0.70 (0.66-0.75) (Table 3).

(Table 3: Cox proportional hazards)

Hazard ratios for women with experience with antihistamines compared to controls adjusted for age and TNM-stage at diagnosis of breast cancer.

Table 4 presents the HR for each antihistamine user group adjusted for age at diagnosis of BC and TNM. Women taking desloratadine had a HR of 0.41 (0.35-0.49). Loratadine users had a HR of 0.64 (0.56-0.72). Cetirizine users had a HR of 0.97 (0.89-1.06) and clemastine users had a HR of 0.69 (0.62-0.77). Ebastin users had a HR of 0.40 (0.27-0.61) and fexofenadine users had a HR of 0.49 (0.29-0.85).

(Table 4: Cox proportional hazards)

Hazard ratios for women with experience using 6 different antihistamines compared to controls adjusted for age and TNM-stage at diagnosis of breast cancer.

late participation model

Univariate Analysis

Women using loratadine, desloratadine and ebastine had a statistically significant longer BC-specific survival compared to controls. Women using cetirizine, clemastine and fexofenadine had a non-statistically significant longer BC specific survival compared to controls ( FIGS. 4 and 5 ). Figure 4. Breast cancer survival according to experience with antihistamines of cetirizine, clemastine and loratadine in a terminal entry model. All cases prior to July 1, 2005 and all women with unknown N-status were excluded from screening. N=14192 in the No AH group, N=2298 in the cetirizine group, N=1777 in the clemastine group, and N=1745 in the loratadine group. Figure 5. Breast cancer survival according to experience with antihistamines of desloratadine, evastin and fexofenadine in a terminal entry model. All cases prior to July 1, 2005 and all women with unknown N-status were excluded from screening. N=14192 in the No AH group, N=1338 in the desloratadine group, N=205 in the ebastine group, and N=97 in the fexofenadine group.

Multivariate Analysis

Table 5 shows the HR for each antihistamine user group adjusted for age at diagnosis of BC and TN. Women who took desloratadine had a HR of 0.69 (0.52-0.91). Loratadine users had a HR of 0.74 (0.60-0.93). Cetirizine users had a HR of 1.13 (0.96-1.33) and clemastine users had a HR of 0.98 (0.80-1.19). Ebastin users had a HR of 0.50 (0.22-1.12) and fexofenadine users had a HR of 0.73 (0.30-1.76). The analysis was also stratified for ER-status, but the results were not significantly different (data not shown).

(Table 5: Cox Proportional Hazards - End-Entry Model)

Hazard ratios for women with experience using 6 groups of antihistamines compared to controls adjusted for age and TN-staging at diagnosis of breast cancer. All cases prior to July 1, 2005 and all women with unknown N-status were excluded from screening.

(Table 6: Cox Proportional Hazards - End-Entry Model. Hazard Ratios for Women by Duration of Use of Desloratadine, Adjusted for Age at Diagnosis of Breast Cancer and TN-Stage.)

(Table 7: Cox Proportional Hazards - Terminal Entry Model. Hazard Ratios for Women as of When Women Used Desloratadine, Adjusted for Age at Diagnosis of Breast Cancer and TN-Stage.)

(Table 8: ER Negative Breast Cancer - Late Entry Model. Hazard Ratios for Women by Breast Cancer ER Molecular Subtype, Adjusted for Age and TN-Stage at Diagnosis of Breast Cancer. Women taking desloratadine were 0.60 (0.45-stage). 0.81).

(Table 9: ER-positive breast cancer - late entry model. Hazard ratios for women according to breast cancer ER molecular subtype, adjusted for age and TN-stage at diagnosis of breast cancer. Women taking desloratadine were 0.62 (0.51-stage). 0.75).

A replicate study was performed as shown in Table 10, using expanded breast cancer data of all cases from the Swedish Cancer Registry 2000-2013 (n=103 500 cases) linking the above data with the drug prescription registry. Due to the large number of cases, higher resolution was achieved, demonstrating better overall and BC specific survival for users of desloratadine or ebastin compared to non-users.

(Table 10: Breast cancer survival and overall survival adjusted for age and divided into two periods 2005-2008 and 2009-2013. Use of different antihistamines after diagnosis in relation to tumor staging. Late entry model.)

Over the years prior to 2009, the survival is significantly improved for desloratadine users compared to non-users, HR = 0.63. The overall effect on better breast cancer survival with desloratadine is summarized in Table 11. It is also very important to note that ceterizine and clemastine negatively affect survival.

(Table 11: Summary of breast cancer survival with desloratadine for 1 year (terminal entry model))

Claims (15)

A pharmaceutical composition comprising desloratadine or ebastine as an active ingredient for use in the treatment of breast cancer in a patient in need thereof, wherein said treatment continues for at least 50 days, wherein the dose of desloratadine is 2.5 to 250 mg, and the dose of ebastin is 2.5 to 500 mg per day. The method of claim 1,
A pharmaceutical composition, wherein the patient is perioperational. The method of claim 1,
The pharmaceutical composition, wherein the patient is further treated with radiation therapy, chemotherapy and/or hormone therapy. The method of claim 1,
wherein the breast cancer is selected from the group consisting of positive and negative ER, PR, her2 breast cancer molecular subtype, and invasive breast cancer. The method of claim 1,
The pharmaceutical composition, wherein the breast cancer is selected from the group consisting of benign and negative ER invasive breast carcinoma. The method of claim 1,
wherein the treatment continues for at least 100 days, or at least 400 days. 6. The method according to any one of claims 1 to 5,
The pharmaceutical composition, wherein the treatment seeks to improve the prognosis for a patient diagnosed with breast cancer. 6. The method according to any one of claims 1 to 5,
The pharmaceutical composition, wherein the treatment seeks to increase the survival time of a patient diagnosed with breast cancer. 6. The method according to any one of claims 1 to 5,
A pharmaceutical composition, wherein the daily dose of desloratadine or ebastin corresponds to the defined daily dose (DDD). 6. The method according to any one of claims 1 to 5,
The pharmaceutical composition, wherein the dose of desloratadine is 2.5 to 45 mg per day, 5 to 20 mg per day, or 5 mg per day. 6. The method according to any one of claims 1 to 5,
The pharmaceutical composition, wherein the dose of desloratadine is 45 to 250 mg per day, 85 to 150 mg per day, or 100 mg per day. 6. The method according to any one of claims 1 to 5,
The pharmaceutical composition, wherein the dose of ebastin is 2.5 to 100 mg per day, 5 to 40 mg per day, or 10 mg per day. 6. The method according to any one of claims 1 to 5,
The pharmaceutical composition, wherein the dose of evastin is 100 to 500 mg per day, 150 to 300 mg per day, or 200 mg per day. 6. The method according to any one of claims 1 to 5,
The pharmaceutical composition, wherein the patient is a patient not diagnosed with a seasonal allergic condition.
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